Melittin (MLT) (10 micrograms/paw) and D49 (0.4 micrograms/paw) were injected into the hind paw of male CD-1 mice and elicited 70-80% of maximal paw edema responses at 60 and 30 min after injection, respectively. D49 paw edema was significantly inhibited by anti-histamine/serotonin agents, a PAF antagonist, a PLA2 inhibitor, and some but not all 5-LO and CO inhibitors, indicating that this edema is produced by several classes of inflammatory mediators with mast cell degranulation apparently playing a major role. In contrast, MLT paw edema was not inhibited effectively using the same pharmacological agents except theophylline, suggesting it was elicited via a different sequence of inflammatory events. In summary, D49 and MLT paw edema models were found to be ineffective models to identify experimental PLA2 compounds in our laboratory.

No abstract

Pretreatment with captopril, a kininase II inhibitor, at 10 mg/kg i.p. or s.c., significantly increased the writhing response induced by a minimum effective dose (0.75 mg/kg i.p.) of phenylbenzoquinone (PBQ), by 91-148%. 1,10-Phenanthroline, a carboxypeptidase B inhibitor (2 mg/kg i.p.), in combination with captopril enhanced the algesic effect of PBQ by 309-360%. Captopril also doubled the number of writhes induced by a minimum effective dose of BK (5 micrograms/kg i.p.) in PGE2-pretreated mice. The writhing responses induced by higher doses of PBQ or BK were not affected by these inhibitors. The hyperalgesic effect of BK (1 micrograms) injected into the hindpaw of rats was significantly increased and prolonged by coinjection of captopril (30 micrograms) and 1,10-phenanthroline (30 micrograms) and was prevented by carboxypeptidase B (1 mg). These data indicate that BK plays a role in pain in these models, a role which appears of greatest relevance at threshold algesic stimulation.

206 ChemInform Abstract Several methods of preparing the title compound (X) from indole derivatives are described. One key intermediate is the (hydroxymethyl)phenylethylindole (IV) which is obtained from isatin (I) and the phenylpropionate (II) or from the indolylacetate (V) and benzyl chloride (VI). (IV) undergoes cyclocondensation with the methoxypentenoate (VIII), forming the dihydropyranoindolylacetates (IX). Saponification of the main diastereomer (IXa) yields pemedolac (X). An alternative pathway to (IX) starts with the oxime (XI) which is hydrogenated and reduced, giving the amino alcohol (XII). This is N-protected and then cyclized with (VIII), producing the fused aminodihydropyran derivative (XV) which is subjected to a complex formylation, dehydration, cleavage, and rearrangement procedure, followed by coupling with benzylmagnesium bromide (XVII), to yield (IX). Pemedolac (X) has analgesic activities. (X-ray analysis of (X) and its (S)-borneol ester).

Histopathologic evaluation of hindpaws from control rats with established adjuvant arthritis showed severe alterations in soft tissue and bone, as well as progressive, moderate‐to‐severe articular changes. Following treatment with etodolac for 28 days, soft tissue and articular changes were rated mild, and bone changes were rated moderate, but with remodeling. These findings indicate that etodolac partially reversed the joint damage in these rats.